Abstract
Immune checkpoint blockers (ICBs) have revolutionized the treatment of multiple malignancies. However, <20% of patients currently benefit from these therapies. Similarly, CAR-T cells have revolutionized the treatment of hematological malignancies but have not been effective against solid tumors. We have demonstrated that this limited efficacy is due to abnormal tumor microenvironment (TME). The dysfunctional tumor vessels not only inhibit infiltration of immune cells (nascent, reactivated with ICBs, or adoptively transferred, such as CAR-T cells) into tumors, but also create a hypoxic and acidic microenvironment that suppresses the function of immune cells after they accrue in tumors. In 2001, I proposed that judicious use of anti-angiogenic agents – that were originally developed to starve tumors – can “normalize” tumor vessels and improve the delivery and efficacy of concurrent therapies. Our preclinical finding that vascular normalization can improve immunotherapy was confirmed by others in phase III trials on combining antiangiogenic therapy with ICBs for lung, kidney, liver, and endometrial, led to the U.S. Food and Drug Administration approvals of seven such combinations for these cancers, and formed the foundation of novel bifunctional antibodies that target both VEGF and PD1/L1. Additionally, we discovered that anti-hypertensive drugs capable of “normalizing” the tumor matrix and stromal cells can reprogram the TME to an immunostimulatory milieu and improve the delivery and efficacy of cancer therapies. A phase II trial led by my clinical collaborators provided evidence in support of this concept for improving the treatment outcome for patients with pancreatic ductal.
Citation: Proceedings of the 7th International Conference on Cell and Experimental Biology (CEB-2026). USG Proc J 2(Suppl 10): S1-S30.
